This project seeks to improve the clinical care available to patients with disorders of ovarian follicle function. In pursuing this goal, we expect to expand basic science understanding of the ovarian follicle in health and disease. We have focused on premature ovarian failure, a condition that prematurely terminates normal ovarian function and fertility in 1% of women. We have particular interest in autoimmunity as a cause of ovarian failure. Our strategies to investigate the mechanisms of premature ovarian failure involve work in the basic science laboratory as well as in the clinic. In a mouse model, we found that autoantibodies from mice with experimental autoimmune oophoritis bind to Mater, a novel 120 kd protein that is specific to the oocyte cytoplasm. Mater is a novel oocyte-specific maternal effect gene whose product we previously demonstrated is essential for embryonic development beyond the two-cell stage. During the past year we defined the human homologue of mouse Mater, a maternal effect gene critical to female fertility. The human and mouse cDNA share 67% homology while their deduced polypeptide chains have 53% identity of amino acids. Also, their proteins have a number of similar structures. Characterization of the human MATER gene and its protein provides a basis for investigating their clinical implications in autoimmune premature ovarian failure and infertility in women. We are now evaluating the antigenic role of Mater in a mouse model of autoimmune ovarian failure. Also, we have generated a mouse line lacking Mater and we are investigating this mouse as a model for human idiopathic infertility. It is well established that patients with spontaneous premature ovarian failure are at increased risk of developing autoimmune adrenal insufficiency, a potentially fatal disorder. There has been ongoing controversy regarding the best clinical strategy by which to detect adrenal insufficiency at an early stage in these young women. We demonstrated that the presence of anti-adrenal antibodies in the serum was highly associated with adrenal insufficiency while a negative test was associated with normal adrenal function in all cases. Our findings demonstrate that measuring adrenal antibodies is an effective screening method by which to detect asymptomatic autoimmune adrenal insufficiency in young women with spontaneous premature ovarian failure. Also, during the past year we found that compared with age-matched contros young women with 46,XX spontaneous premature ovarian failure have an increased prevalence and severity of both signs and symptoms of ocular surface disease. It is possible that the dry eye phenotype may signal a particular mechanism of premature ovarian failure, such as autoimmunity, since not all patients have dry eye syndrome. It is also possible that endocrine factors, such as the androgen deficiency associated with premature ovarian failure, might explain the association. Additional studies are planned to further characterize this pathology and determine its etiology. In an ongoing study we are evaluating the role of physiologic testosterone replacement for young women with premature ovarian failure. The normal human ovary produces small amounts of testosterone that currently is not replaced as part of standard clinical practice. We are conducting a 3-year prospective, randomized, placebo-controlled trial of adding physiologic testosterone replacement using a transdermal delivery system. Bone density is the primary outcome parameter.